Between June 2002 and January 2018, patients who were diagnosed as LS-SCLC, had achieved CR or PR after definitive chemoradiotherapy but did not receive PCI were included in this study. The following patients were excluded: diagnosed as mixed SCLC, received surgical treatment except pathological biopsy, have a history of other malignant tumors, patients who were lost to follow-up after treatment. Demographic variables, which were obtained from medical records on the electronic database of Zhejiang Cancer Hospital, included age, gender, Karnofsky Performance Status (KPS), and so on. All data access was approved by the Ethics Committee of Zhejiang Cancer Hospital (IRB-2022-758).

Chemotherapy consisted of etoposide 100mg/m² d1-3, cisplatin 80mg/m² d1 or 25mg/m² d1-3, or carboplatin AUC=5 d1, repeated every 3 weeks for 4-6 cycles.

All patients received accelerated hyperfractionated radiotherapy consisted of 1.5 Gy twice daily in 30 fractions to 45 Gy, and the interval between fractions was ≥6 hours.

Patients received chest and abdominal enhanced CT and brain enhanced MRI 4-6 weeks after chest chemoradiotherapy, for those who had achieved CR or PR, PCI was recommended. The prescribed dose of PCI was 25Gy in 10 fractions.

Patients were reviewed every 3 months in 2 years after chemoradiotherapy, every 6 months in 3 to 5 years, and then once every year after 5 years. Physical examination, enhanced CT of chest and upper abdomen were performed routinely. The frequency of brain MRI (first choice) or brain CT or positron emission computed tomography was at the discretion of the physician. Brain metastases were determined by brain MRI or CT imaging features. After treatment of BM, patients were reviewed every 2 months in the first year, then every 3 to 4 months in the second to third year, and every 6 months thereafter.

In this study, OS was defined as the time from the end of chemoradiotherapy to death or last follow-up. Statistics and graphing were conducted using SPSS 25.0 and GraphPad Prism 8.0 software. The two-tailed t-test was used for continuous variables. Mann-Whitney U test was used to compare non-normally distributed data. Categorical variables were compared using the X² test. The survival outcomes were calculated using the Kaplan–Meier method. The Cox proportional models were applied for univariate and multivariate prognostic analyses. Propensity score-matching (PSM) was performed using the R MatchIt package for Windows version. A two-tailed value of p < 0.05 denoted statistical significance.

The propensity score was calculated using multivariable logistic regression to model a dichotomous outcome of PCI or non-PCI. In an initial analysis, patients in the PCI and non-PCI groups were compared based on age, gender, KPS, AJCC Staging and curative effect. The subjects were 1:1 matched by the estimated propensity score with a caliper of 0.02 of the logit of the propensity score.

From June 2002 to January 2018, 500 patients with LS-SCLC were admitted, of which 362 (72.4%) received definitive chest radiotherapy and chemotherapy. According to Response Evaluation Criteria In Solid Tumors (RECIST), 137 cases (37.8%) had achieved CR and 190 cases (52.5%) had achieved PR after chemoradiotherapy. Among the patients who achieved CR and PR, 103 cases (31.5%) did not receive PCI. 63 patients (61.2%) developed BM, of which, 19 patients (30.2%) had BM detected by brain MRI before PCI. By the last follow-up date (June 25, 2022), a total of 172 patients had follow-up data, of whom 98 had received PCI and 74 had not received PCI. The matching process resulted in a final cohort of 96 patients. Each cohort comprised 48 patients. The eligible patients in two groups were similar in terms of age (median: 64 vs. 62 years, respectively), gender, KPS (median: 90 vs. 90, respectively), AJCC stage, and curative effect ( Table 1 ).

In the 74 patients who did not receive PCI, 40 patients developed brain metastases. These BM patients had regular follow-up data after treatment were analyzed, as shown in Table 2 . The median interval time between the discovery of BM and the initial treatment was 5.6 months (range: 2.9-26.6 months), and the median interval time between the discovery of BM and the completion of chemoradiotherapy was 1.6 months (range: 0.2-24.2 months). Among the 9 patients who received radiotherapy combined with chemotherapy, 5 patients received whole brain radiotherapy (WBRT), 3 patients received WBRT plus focal radiation boost, and 1 patient received X-knife. Among the 23 patients who received brain radiotherapy alone, 7 patients received WBRT, 9 patients received WBRT plus focal radiation boost, 1 patient received γ-knife therapy, and radiotherapy technique in 6 patients was unknown. Four patients received chemotherapy alone. Four patients did not receive any treatment.

By the last follow-up (June 25, 2022), 30(62.5%) patients had died in PCI group, and 39(81.3%) patients had died in non-PCI group, respectively. All of which were related to disease progression. The median follow-up time was 18.4 months (range: 0.7-76.6). The 1-year and 3-year OS rates in PCI group were 87.5% and 42.3% respectively, versus 70.4% and 20.9% for non-PCI group(P=0.002), as shown in Figure 1A . The 1-year and 3-year BM-free rates in PCI group were 97.9% and 93.3% respectively, versus 64.4% and 46.4% for non-PCI group(P<0.001), as shown in Figure 1B .

Before PSM, 40 patients with BM in non-PCI group, 38 patients had died, all of which were related to disease progression. However, 34 patients without BM in non-PCI group, 24 patients had died, all of which were related to disease progression. The median follow-up time of 40 patients with BM were 12.5 months (range: 0.7-53.1), and the median survival time was 12.5 months (range: 0.7-53.1). The median follow-up time of 34 patients without BM was 14.4 months (range: 0.8-61.4), and the survival time was 15.3 months (range: 0.8-61.4). The 1-year and 3-years OS rates in BM group were 60.0 and 15.0% respectively, versus 60.7% and 33.4% for non-BM group (P=0.014), as shown in Figure 2 . The median survival time of BM patients with well controlled and out of controlled extracranial disease were 9.0 months (range: 0.3-48.7) and 6.7 months (range: 0.9-35.2).

For 74 patients in non-PCI group, univariate and multivariate analysis were used to determine the prognostic value of clinical risk factors affecting BM, as shown in Table 3 . Patients whose age ≤61 years were more likely to develop BM than patients > 61 years of age(P=0.007). Patients whose KPS <90 were more likely to develop brain metastases than those whose KPS ≥90(P=0.005). For 40 patients with BM in non-PCI group who received palliative treatment, OS was defined as the time from the diagnosis of BM to death or last follow-up. The median survival time of patients who received radiotherapy combined with chemotherapy, radiotherapy alone, chemotherapy alone and no treatment were 19.7 months (range: 5.0-48.7), 10.4 months (range: 2.0-27.7), 7.0 months (range: 2.2-12.7) and 2.0 months (range: 0.3-6.7), respectively. Log-rank test indicated that patients who received radiotherapy alone or chemoradiotherapy both had significantly higher OS rates than untreated patients (chemoradiotherapy vs. untreated, P=0.005; Radiotherapy alone vs. untreated, P < 0.001). There was no significant difference in OS between patients who received chemotherapy alone and no treatment (P=0.085). Compared with monotherapy, combined therapy significantly improved OS (radiotherapy combined with chemotherapy vs. radiotherapy alone, P=0.022; Radiotherapy combined with chemotherapy vs. chemotherapy alone, P=0.025). There was no significant difference in OS between the two monotherapies (radiotherapy alone vs. chemotherapy alone, P=0.095), as shown in Figure 3 .

Variables such as age, gender, the interval time between BM and the initial treatment, whether multiple BM and the treatment modalities adopted after BM were included in the univariate Cox regression analysis. The results suggested that symptomatic BM, receiving brain radiotherapy alone and receiving radiotherapy combined with chemotherapy were significantly correlated with OS. Variables with P < 0.2 in univariate analysis were included in multivariate Cox regression analysis. The results showed that, compared with no treatment, patients received brain radiotherapy alone (HR: 0.131, 95%CI: 0.035-0.491, P=0.003), radiotherapy combined with chemotherapy (HR: 0.039, 95%CI: 0.008-0.194, P < 0.001) significantly reduced the risk of death. Multiple BM (HR: 2.391, 95%CI: (1.082-5.285), P=0.031) was an independent adverse prognostic factor for OS, as shown in Table 4 .